1. Field of the Invention
The present invention relates to pharmaceutical compositions in the form of self-emulsifying systems. More particularly, the present invention is directed to pharmaceutical compositions, preferably cyclosporin compositions, which form an emulsion in the presence of aqueous media and environments, for example, water and gastrointestinal fluids.
2. Discussion of Background Information
Cyclosporins form a class of polypeptides well known for possessing immunosuppressive and anti-inflammatory activity. The most commonly known cyclosporin is cyclosporin-A, which is commercially available as Sandimmune® and Neoral® in soft gelatin capsule dosage form and as a liquid drink-solution.
Cyclosporins are hydrophobic substances exhibiting poor water solubility and unsatisfactory bioavailability. Oral liquid formulations containing oil, ethanol, and a surfactant such as LABRAFIL®, which is a transesterification product of a triglyceride and a polyol, are disclosed in U.S. Pat. No. 4,388,307. However, these formulations are characterized by a variety of disadvantageous properties, including unpleasant taste, which make these formulations undesirable for long-term therapy. Encapsulation in soft gelatin capsules improves the taste-acceptability of the liquid, but because of the presence of the hydrophilic component (ethanol) in the capsules, they must be packaged in specialized, expensive airtight blister or aluminum foil blister packs. The bioavailability of these liquid and soft gel formulations is low (approximately 30%) and also variable.
U.S. Pat. No. 5,342,625 discloses cyclosporin formulations indicated to have enhanced bioavailability. In addition to cyclosporin, the formulation disclosed in this patent includes a hydrophilic phase, a lipophilic phase, and a surfactant. The hydrophilic phase comprises either 1,2-propylene glycol or an ether of the formula R1—(—O—(CH2)2)x—OR2, wherein R1 is alkyl or tetrahydrofurfuryl, R2 is alkyl, tetrahydrofurfuryl, or hydrogen, and X is an integer of 1 to 6. Such ethers are commercially available under the trademarks TRANSCUTOL®, COLYCOFUROL, and GLYCOFUROL®. The hydrophilic phase may additionally contain C1-C5 alkanols, such as ethanol. The formulation disclosed in U.S. Pat. No. 5,342,625, therefore, like those of U.S. Pat. No. 4,388,307, requires special packaging, such as aluminum foil blister packs. Further, ethers in the formulations disclosed in U.S. Pat. No. 5,342,625, such as the indicated TRANSCUTOL® and GLYCOFUROL®, are restricted by several regulatory agencies worldwide, including the United States Food and Drug Administration, because these compounds are not considered “generally recognized as safe” (G.R.A.S.) for oral use.
U.S. Pat. No. 5,154,930 discloses lipophilic drug compositions which form suspensions of lipid aggregates when introduced to an aqueous phase and agitated. Illustrations of the invention include compositions of cyclosporin A. The compositions comprise a non-aqueous water-miscible solvent (hydrophilic phase), preferably ethanol or polyethylene glycol. The compositions also require a desalted charged lipid which is soluble in the water-soluble solvent, and which exhibits limited sedimentation upon dispersal in the aqueous medium of suspension formation.
There is a need for improved formulations that can be inexpensively and conventionally packaged, such as in glass or O.H.D. polyethylene bottles. There is also a need for formulations, e.g., oral formulations, whose components comprise only G.R.A.S. excipients.
Alcohol-free pre-emulsion concentrates are known, but also have flaws. For example, the formulation of U.S. Pat. No. 5,206,219 requires a multitude of ingredients, including a protease inhibitor, cholesterol, a phospholipid, a surfactant, a polyol, and a lipid solvent.
U.S. Pat. No. 4,990,337 discloses solutions of cyclosporin in monoglycerides or diglycerides of C6 to C10 fatty acids, preferably in a C8 diglyceride, which can be emulsified in water. All of the examples describe preparing emulsions by making two solutions—one containing cyclosporin and a fatty acid glyceride, and the other containing water with a small amount of surfactant—mixing the solutions, and emulsifying them with laboratory equipment. Although Test Example 2 discloses that capric acid monoglyceride, when shaken with water, would emulsify in a manner “very close to self-emulsification,” there is no teaching or suggestion of how to prepare a cyclosporin composition which forms a fine emulsion on contact with an aqueous phase.
U.S. Pat. No. 5,759,997, discloses compositions comprising cyclosporin, a mixture of mono-, di-, and triglycerides, and a hydrophilic tenside. In one embodiment, the mixture of mono-, di-, and triglycerides comes from a single product, such as MAISINE®, whose fatty acid component is mainly long chain. There is no suggestion that these compositions would self-emulsify, nor is there any discussion of how to prepare a cyclosporin composition which forms a fine emulsion on contact with an aqueous phase.